ABSTRACT Addiction to therapeutic opioid drugs and heroin has seen a marked increase in the US during the past two decades. In 2014, therapeutic opioid overdose and heroin were responsible for 18,893 and 10,574 deaths respectively. Opioid overdose is the primary driver for drug poisoning, being the leading cause of accidental death in the US, with 47,055 fatalities in 2014. The UCLA Center for Study of Opioid Receptors and Drugs of Abuse (CSORDA) has a focused multidisciplinary preclinical opioid research program with a broader educational and outreach mission in the area of addiction. Mu opioid receptors are targets for many addictive disorders since they are key components for mediating the rewarding effects of opiates, nicotine, cannabinoids, alcohol and food. CSORDA?s research program focuses on elucidating the circuitry and cell-specific adaptations underlying addiction-related behaviors mediated by mu opioid receptors. This CSORDA renewal application (years 31-36) focuses on understanding the circuitry regulating dysphoric states and investigates different opiate addiction susceptibility models, including neuropathic pain, opioid withdrawal and PTSD. The research plan will build upon progress during the past funding period by incorporating several CSORDA-developed innovative genetic mouse models, findings with regards to resting state fMRI imaging, as well as the elucidation of circuitry regulating opioid reward via neuroinflammation and perturbation of D2 enkephalinergic systems. The renewal will use a model of PTSD to examine the marked comorbidity of this disorder with addiction to drugs reliant on the endogenous opioid system for reward-related behaviors. To maintain CSORDA as a technically cutting edge and innovative Center, we have created a Technical Advancement Core (TA-Core) that will enable CSORDA?s research plan to incorporate new technologies optimized and vetted for CSORDA research. Four Research Projects are proposed that are highly interactive, both thematically and technically, and which use shared models, reagents and methods. Projects will focus on different brain circuitry associated with addiction, including the mesolimbic VTA striatal reward system (Projects I and III), the habenula (Projects II and III) and the amygdala (Project IV). Research Projects will explore the modulation of circuitry in models of chronic pain (Project III), withdrawal and depression (Projects I, II and III) and PTSD (Project IV). The research will employ mouse genetics and behavioral analysis combined with electrophysiology, optogenetics, transcript analysis and MRI imaging. In addition to the TA-Core, CSORDA will support an Animal Breeding Core (AB-Core) supplying all CSORDA Projects with mouse models and sharing reagents with the research community. The Administrative Core and CSORDA Advisory Board, consisting of Drs. Bernard Balleine, Antonello Bonci, Charles Chavkin, Pat Levitt, Eric Nestler and Peter Whybrow ex-officio, will provide programmatic oversight and coordinate training, outreach and a vigorous Pilot Program.